Interaction of pemetrexed disodium (ALIMTA, multitargeted antifolate) and irradiation in vitro

Bischof, Marc; Weber, Klaus-Josef; Blatter, J.; Wannenmacher, M; Latz, D.

doi:10.1016/s0360-3016(01)02794-8

Cited by 65 publications

(48 citation statements)

References 21 publications

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“…PMX has been used in combinations with gemcitabine, tyrosine kinase inhibitors, antibodies, or even external radiation (22)(23)(24). A combination of PMX with external radiotherapy was based on the observation that PMX acts as a radiosensitizing agent in variable types of cancer cells in vitro and in vivo (25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

Reber

Haller

Leamon

et al. 2013

Molecular Cancer Therapeutics

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Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folatebased radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate 177 Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of 177 Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI < 0.8). In an in vivo study, tumor-bearing mice were treated with 177 Lu-EC0800 (20 MBq) and a subtherapeutic (0.4 mg) or therapeutic amount (1.6 mg) of PMX. Application of 177 Lu-EC0800 with PMX ther resulted in a two-to four-fold enhanced tumor growth delay and a prolonged survival of KB and IGROV-1 tumor-bearing mice, as compared to the combination with PMX subther or untreated control mice. PMX subther protected the kidneys from undesired side effects of 177 Lu-EC0800 (20 MBq) by reducing the absorbed radiation dose. Intact kidney function was shown by determination of plasma parameters and quantitative single-photon emission computed tomography using 99m Tc-DMSA. Our results confirmed the anticipated dual role of PMX. Its unique features resulted in an improved antitumor effect of folate-based radionuclide therapy and prevented undesired radio-nephrotoxicity. Mol Cancer Ther; 12(11); 2436-45. Ó2013 AACR.

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Section: Introductionmentioning

confidence: 99%

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

Reber

Haller

Leamon

et al. 2013

Molecular Cancer Therapeutics

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“…Antifolates have been established in cancer treatment for many years and are widely used in combination with radiotherapy (29). The ability of Pemetrexed to sensitize cells to ionizing radiation was reported in preclinical studies (30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy

et al. 2005

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It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G 1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 F 2.6 to 4.2 F 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/ chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy. (Cancer Res 2005; 65(9): 3643-55)

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“…Furthermore, in preclinical studies, the combination of pemetrexed with concurrent radiation showed synergistic activity (30). An enhancement ratio of 1.6 was reported for a lung cancer line (1.2-1.8 for other tumor types), with a tendency towards higher ratios with increasing pemetrexed concentrations.…”

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confidence: 94%

A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

Seiwert¹,

Connell

Mauer³

et al. 2007

Clinical Cancer Research

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Purpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. Experimental Design: Patients with locally advanced or metastatic non^small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m 2 ); regimen 2 was pemetrexed (500 mg/m 2 ) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m 2 ). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m 2 ; AUC = 6); grade 3/4 leukopenia (4 of12 patients) was the mainhematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed.When systemically active chemotherapy doses were reached, further dose escalation was discontinued, and a phase IIdose-range was established (pemetrexed 500 mg/m 2 and carboplatin AUC = 5-6). Conclusions: The combination of pemetrexed (500 mg/m 2 ) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.

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Interaction of pemetrexed disodium (ALIMTA, multitargeted antifolate) and irradiation in vitro

Cited by 65 publications

References 21 publications

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy

A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

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